One of the attractions of fragment-based screening is based on the observation “Fragment Space” is smaller than “Chemical Space” and can be more effectively probed with a relatively small library
- A million compounds cover only a small fraction of the suggested 1060 Chemical Space, whilst 2000 compounds can probe much of the 106 Fragment Space
Several approaches have been described in the design of fragment libraries. Most comply with the commonly accepted Astex "Rule-of-Three" (MW <300, H-bond donors/acceptors <=3, cLogP <3). Ideally they should also have solubility measure.
One approach for choosing compounds to be included in the fragment collection is to take a collection of biologically active compounds (e.g. known drugs) and fragment them (e.g. RECAP from CCG), the most common fragments containing 8 or more heavy atoms are then used to search commercial compound collections.
An alternative approach is to take common frameworks or privileged structures (e.g. biphenyl) and decorate them with small functional groups (carboxylate, amine, hydroxyl, halo).
Whilst many companies of samples for screening an increasing number of commercial companies are now offering well defined fragments for screening, as might be expected there is significant overlap between the various companies however most also contain unique fragments.
Fragment Libraries with details taken from the company websites.
AnCoreX
AnCore’s fragment libraries consists of 500-1000 fragments specifically targeting metallo-protein active sites. More than one-third of proteins contain a metal ion.
Asinex
BioFragments comprises of 1800 especially small compounds ideal for fragment-based screening. These compounds are in essence bare templates that have been carefully decorated with ‘small caps’ - very low molecular weight peripheral building blocks. Molecu;ar Weight 120-250, cLogP <2.5, HAC 9-18, HBA < 7, HBD <4. Asinex also provide a fragment to lead set designed for fragment growth and elaboration.
ChemBridge
The Fragment Library set, comprising approximately 12,000 compounds, was chosen based upon the commonly accepted Astex "Rule-of-Three" (MW <300, H-bond donors/acceptors <3, cLogP <3) as well as the established proprietary ChemBridge substructure filters. The set includes compounds with available, as well as protected, functionality. All compounds in the collection are available in stock and may be cherry-picked or taken as a complete set.
ChemDiv
The current library contains nearly 5000 compounds, molecular weight 96 to 301, HBA <6, HBD <5, logD -8.0 to 5.17 and are predicted to have good water solubility. The fragments selected contain only C, H, N, O, S, P, F, Cl, and Br atoms. Fragments with undesirable properties are eliminated by applying our special medicinal chemistry filters. The library contains 615 unique heterocycles.
Enamine
The Enamine Fragment Library was designed by application of "Rule of three" filters proposed by Astex Therapeutics [7] and then strict structural filters [8] to a combined dataset of Enamine Screening Compounds and Building Blocks (940,000 and 19,000 respectively at the time of the library preparation). Criteria used in ADME selection are summarized in Table 1. We had identified 6,173 compounds strictly meeting these requirements. Analysis of this set by the variable-length Jarvis-Patrick clustering (Tanimoto coefficient – 0.85, portion of near neighbors overlapping – 0.5) resulted in 830 clusters and 1819 singletones, which were refined by stringent scientific expertise to yield 1190 structures of the Fragment Library.
InFarmatik
We now offer 300 diverse 3-D fragments from stock and a Synthesis OnDemand fragment library based on validated chemistry which contains over 8400 new and diverse 3-D fragments. In addition we have a set of 293 in-stock Ro3 compliant 2-D fragments.The 3-D fragment compounds are not common experimental substances. They were specifically designed as fragments and not just filtered out from publicly available compound sets, as many of our competitors have done. About half of them are diverse spiro shape compounds. They are new and original, therefore their IP field is still not overloaded, making them easily patentable. Most of the compounds have soft scaffold structures: meaning they were designed to have low reactivity centers to avoid non-specific binding, while preserving the ease of chemically coupling them to each other or to other fragments. All non-specific binding groups (strong acids, bases and reactive moieties) are omitted. The attachment points in the molecules in many cases are useful for region specific reactions. Some of the fragments fit the criteria of being scaffolds as well. Average MW=238, average clogP=1.6, confirmed experimental water solubility in 0.1% in 2% aqueous DMSO with stability data. We also offer custom fragment analog synthesis and fragment coupling services.
IOTA
Fragments in IOTA's "Diverse 1500" Library have been specifically synthesised to cover "diverse" chemical space. The majority of these fragments are unique to IOTA – they cannot be purchased elsewhere. Most of the fragments are soluble at 1mM, obeying the Astex "Rule of 3".
Key Organics
The Bionet Fragment Library Ro3 encompasses 7,025 carefully selected diverse fragments which have been rigorously chosen for their suitability for fragment based screening applications and further chemical elaboration. It has been established that 3,228 of these fragments are uniquely available through Bionet.
Life Chemicals
In this part of our collection we present lead-like compounds, which are selected according to the following criteria:- MW less than 300, - clogP less than 3. We have over 32000 such compounds including 22000 in stock. Also, we offer a more narrow selection of fragments, applying additionally the following criteria:-Rotatable bond count less than 5, HBA less than 3 and HBD less than 2, Topological polar surface area less than 70 A. Of such compounds we have 9000 in stock and 2900 tangible. These compounds of special interest for those of our customers, who are in fragment based drug discovery.
Maybridge
The Maybridge Ro3 Fragment Library: A set of 1000 premier fragments developed as part of our 45 year pedigree in delivering novel, pharmacophorically rich molecules. The Maybridge Ro3 Fragment Library benefits from a number of key features such as high purity (≥95%). Rule of Three (Ro3) compliance, quantifiable diversity through the application of industry standard chemometrics, assured aqueous solubility to ≥ 1mM using ALogGPS (VCCLab) with outliers confirmed by actual solubility measurement.
Full analytical data is available on request. The result is a unique tool for efficiently probing structural space within your target protein. Click here to download the Ro3 Fragment flyer. The Maybridge Ro3 500 Fragment Library: A set of 500 fragments extracted from the Maybridge Ro3 Fragment Library which incorporates all of the benefits of its larger parent library. The Maybridge Ro3 500 Fragment Library has been developed to meet the needs of the customer who wants the convenience of a preselected high value fragment product but is looking for a small scale, cost effective entry point into fragment based drug discovery.
Otava
Strict structural, substructural and special medicinal chemistry filters were applied for the library preparation. The OTAVA’s Fragment Library, comprising approximately 3,800 compounds, has been designed based upon the commonly accepted "Rule-of-Three" and other physicochemical and structural properties. Compounds were filtered on molecular weight (MW <300); number of H-bond donors ≤ 3; hydrophobicity as the calculated octanol/water partition coefficient (cLogP <3); number of rotatable bonds ≤ 3; number of H-bond acceptors ≤ 4 (the increased number of acceptors in the library was applied to satisfy a kinase binding pharmacophore); molecular polar surface area (PSA < 80); calculated aqueous solubility (LogSW > -5) (high aqueous solubility is essential for practical reasons during screening particularly in HCS).
Prestwick Chemical
The Prestwick Fragment Library is composed of 2786 compounds all carefully selected to match in an optimal way the requirements for fragment based screening techniques. The library contains a MW < 300 set of known drugs, together with a perfectly designed collection of new fragments derived from drug molecules. These compounds are optimized to exhibit high ‘Rule of three’ compatibility. All compounds are in stock, and are available as a complete Library in powder form, or may be cherry-picked.
Pyxis
Pyxis Discovery has designed and synthesized a library of fragments, which are based on scaffolds that are found in existing drugs. These novel and unique fragments are ‘Rule of 3’ compliant, diverse, filtered for undesirable chemistry and have built-in possibilities for follow-up chemistry. The Smart fragment library provides excellent starting points for fragment evolution programs and is suitable for any fragment screening platform.
Selcia
A 1300 compound library designed to be ‘rule of 3’ compliant, with high degree of diversity and with the added advantage of > 1mM measured solubility. All shown to be >95% purity by LC-MS and NMR. A poster describing the design and profile of the Selcia library I helped design is available here. This library was designed specifically for the CEFrag screening technology and is not currently available for purchase.
TimTec Fragment-Based Library, FBL, gathers structurally diverse ligands with well suited chemical-physical properties for FBDD screening. Compounds are delivered in dry form in custom milligram or micromolar amounts and as freshly prepared DMSO solution aliquots. One of the preferred concentrations for FBDD is up to 1.5mM with small volume (1-25-30-50uL) per well. Compound selection criteria for FBDD overlaps in chemical-physical properties and screening techniques, yet is more encompassing and specific, than compound selection criteria for the Rule of Three and, so called, Reduced Complexity Criteria.
Zenobia
In general, the screening libraries contain ~1000 compounds and have been optimized to cover as much diversity space as possible given the target class restrictions.
If you are building up a collection from commercial suppliers then it is worth reading the Chemical Databases and Suppliers page.
Updated 18 November 2011
See also Fragment Based Screening
See Also Fragment Collection Profiles
See also Known Fragment Hits
Back to Drug Discovery Resources